The long-term goal of this project is to better understand skin regeneration following wounding in adults. We discovered that after a full thickness wound on the back skin of an adult mouse, hair follicles form de novo. These new follicles reestablish their stem cell niche, produce hair, and cycle. This regeneration resembles embryonic hair follicle development morphologically and molecularly, and occurs several days after wound closure and reepithelialization. Inhibition of wnt prevents hair follicle neogenesis, while wnt overexpression enhances hair follicle formation. The major goal of this grant is to further characterize hair follicle neogenesis and understand the molecular signals controlling this phenomenon. We hypothesize that adult mammals, including humans, have the capacity to regenerate epidermal adnexal structures, such as hair follicles and sebaceous glands, and that this regeneration can be enhanced or inhibited by manipulating pathways known to be important for hair follicle development. Our aims are to study the effects of aging, hair cycle, minimum stimulus required for neogenesis, and whether neogenesis occurs in human skin grafted to immunodeficint mice. We will also define the role of adult stem cell populations in the skin for their ability to contribute to hair follicle neogenesis. Lastly, we will examine the role of growth factors known to be necessary for hair follicle development in follilce neogenesis. We will use global gene expression patterns to assist with our analysis and effort to discern the molecular pathways necessary for neogenesis so that we can eventually manipulate these pathways to improve wound healing. We will use transgenic and knockout mouse technology to evaluate the function of candiadate genes necessary for hair follicle regeneration. Our results should have major implications for understanding skin biology and developing future treatments for wounds, alopecia and other degenerative skin disorders.